This Fast Track SBIR grant proposal seeks to develop a new class of macrocylic peptide drugs for treatment of systemic candidiasis, an increasingly frequent cause of serious and often fatal infections in hospitalized and immunosuppressed patients. Mortality rates associated with these infections have risen sharply due to the emergence of multidrug resistant (MDR) strains of C. albicans and other Candida spp. Currently, there are but three classes of antifungal drugs available for treatment of invasive fungal diseases (polyenes, azoles, and echinocandins), and it has been nearly two decades since the last new class of antifungals (echinocandins) was approved. MDR isolates of Candida spp. that are resistant to all azoles and echinocandins are increasingly common, highlighting the urgent need for new antifungal therapeutics. This project seeks to develop a new class of proprietary antifungal peptides, OrynotidesTM, the design of which was bioinspired by ?-defensins, cyclic host- defense peptides expressed in Old World monkeys but not humans. A lead series of 35 Orynotides, down- selected from a larger proprietary library, is composed of macrocyclic peptides that are potently fungicidal against clinical isolates of MDR C. albicans and other pathogenic Candida spp., including C. auris a highly virulent globally emerging pathogen. Each of the Orynotide candidates has been prequalified as being fungicidal, highly stable in biological matrices, stable to proteases in fungal lysates, non-toxic to mice, and readily manufacturable. Among the prequalified Orynotides are compounds that markedly enhance survival in two models of systemic candidiasis including infections caused by caspofungin resistant C. albicans and MDR C. auris. Based on these findings, we propose in Phase 1 of the project to identify at least three peptides (from the prequalified panel of 35 Orynotides) that are equal or superior to a reference Orynotide that is effective in murine C. albicans candidiasis. Comparative efficacy metrics will include enhanced survival, reduction of fungal burden, and maintenance of body weight. Achievement of this Phase 1 milestone would trigger Phase 2 studies. The first of two Phase 2 Aims will identify a lead Orynotide, from 3-5 lead finalists, for preclinical development based on therapeutic efficacy, safety, and exposure-response analyses in immunocompetent and neutropenic mice. Phase 2 studies will then focus on IND enabling GLP toxicology studies of the lead Orynotide, with the goal being to file an IND by the end of the third year of Phase 2. Completion of this objective will position the applicant and its partners to introduce a new class of antifungal drugs for treatment of systemic candidiasis. This would represent the first new antifungal class to be introduced for human mycoses in nearly two decades.